Causa morbis ignota: A History of Lupus

This is a guest post written by Dr. Christine Konya, a fellow in Rheumatology at Beth Israel Deaconess Medical Center. She studies T cells in lupus.

“We cannot say here causa mortis ignota [cause of death is unknown] but I should say causa morbis ignota [cause of the disease is unknown].” [1]

Dr. Cabot a physician at Massachusetts General Hospital was quoted as saying these words in an article published by the Boston Medical and Surgical Journal in May 1924. Today, this journal is known as the New England Journal of Medicine, officially renamed in 1928. Dr Cabot was referring to a patient that likely had systemic lupus erythematosus. Back in those days, the disease was treated by dermatologists given the characteristic skin findings. The systemic features of lupus were not fully understood. At that time, the disease was known as “disseminated lupus erythematosus,” considered to be associated to an infection such as tuberculosis, hence the word ”disseminated.”

In the same journal article, the confusion between TB and the new, partially described “disseminated” form of lupus erythematosus is apparent:

“-Dr. Means: What kind of skin tuberculosis did the skin people think this was?
-An Interne: Disseminated lupus erythematosus.
-Dr. Means: I thought lupus erythematosus was not a tuberculous disease at all.
-An Interne: It is thought not, but the disseminated form is.”

The idea of autoimmunity, diseases in which self-tolerance is broken, was completely unknown at that time, and the field of immunology barely existent.

Over the years, the systemic form of “lupus erythematosus” became evident. In an article published April 1934 by the New England Journal of Medicine, the disseminated form was described as the following:

“The following symptoms of acknowledged import occurred: erythematous cutaneous lesions, rheumatoid pains, hemorrhagic tendencies, high fever, and leucopenia. Roxburgh says that these fatal cases start from a chronic, localized type, that they are more frequent in women, and that they usually occur between the ages of 20 and 30 years. The presence of arthritis, arthralgia, muscular pains, albuminuria, a purpuric eruption, and a high fever are of bad prognostic significance and suggest the onset of a fatal ending. Death occurs in from one to four months after the beginning of these symptoms.” [2]

A few years later, in November 1938, a Boston dermatologist by the name of Dr. Tolman published the following description about lupus erythematosus in the same journal. A description of lupus which remains relevant almost 100 years later:

“It is generally accepted that there are four main clinical types of lupus erythematosus: the chronic discoid or fixed, the chronic disseminate, the subacute disseminate and the acute disseminate. The present paper deals exclusively with the discoid or fixed type. This form occurs chiefly on the face (where it characteristically attacks the bridge of the nose and the flush areas of the cheeks, the so-called butterfly outline), ears, mucous membranes and scalp. The early lesion is an erythematous and slightly elevated macule The course of the disease is chronic, afebrile and benign, in contrast with the disseminate forms, which are acute in onset, and are associated with fever and a multitude of pathologic findings, and which are only too frequently fatal.” [3]

Slowly, the field of immunology evolved, but the diagnosis of lupus erythematosus was still challenging to make in the absence of serologic markers. It was not until the late 1950’s when anti-nuclear antibody (ANA) was detected in patients with lupus, and it gradually became part of its diagnosis.

In regards to treatment, not much was available until the discovery of cortisone, for which Reichtein, Kendall, and Hench were awarded the Nobel Prize in 1950. Treatment with antimalarials began in 1951 with quinacrine. Both drugs significantly increased quality of life and life expectancy. These medicines are still the backbone of lupus therapy to this day, although other drugs are also being used to manage disease activity.

We now have a better understanding of lupus and autoimmunity in general. We know that an imbalanced immune system with malfunctioning immune cells are the cause of tissue inflammation. It is likely that the disease we call systemic lupus erythematosus is actually a group of related disorders, not a single disease entity. However, we are still working to decipher how and why immune cells lose tolerance to self-antigen, and how the intracellular signaling cascades lead to an abnormal inflammatory response.

Treatment options for most rheumatic diseases have dramatically increased over the last two decades, also becoming more effective with the development of targeted therapy with biologics. In contrast, treatment for lupus has not yet entered its renaissance. Biologics did not meet our expectations in controlling disease, but research is rapidly evolving. The goal remains to develop personalized and target treatment options to control and eventually cure disease.

I still think that Dr. Cabot’s words from 1924 still hold true today: “Causa morbis ignota,” the cause of the disease is unknown.